Regional Practice Variation and Outcomes in the Standard Versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) Trial: A Post Hoc Secondary Analysis

OBJECTIVES: Among patients with severe acute kidney injury (AKI) admitted to the ICU in high-income countries, regional practice variations for fluid balance (FB) management, timing, and choice of renal replacement therapy (RRT) modality may be significant. DESIGN: Secondary post hoc analysis of the STandard vs. Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial (ClinicalTrials.gov number NCT02568722). SETTING: One hundred-fifty-three ICUs in 13 countries. PATIENTS: Altogether 2693 critically ill patients with AKI, of whom 994 were North American, 1143 European, and 556 from Australia and New Zealand (ANZ). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total mean FB to a maximum of 14 days was +7199 mL in North America, +5641 mL in Europe, and +2211 mL in ANZ (p < 0.001). The median time to RRT initiation among patients allocated to the standard strategy was longest in Europe compared with North America and ANZ (p < 0.001; p < 0.001). Continuous RRT was the initial RRT modality in 60.8% of patients in North America and 56.8% of patients in Europe, compared with 96.4% of patients in ANZ (p < 0.001). After adjustment for predefined baseline characteristics, compared with North American and European patients, those in ANZ were more likely to survive to ICU (p < 0.001) and hospital discharge (p < 0.001) and to 90 days (for ANZ vs. Europe: risk difference [RD], –11.3%; 95% CI, –17.7% to –4.8%; p < 0.001 and for ANZ vs. North America: RD, –10.3%; 95% CI, –17.5% to –3.1%; p = 0.007). CONCLUSIONS: Among STARRT-AKI trial centers, significant regional practice variation exists regarding FB, timing of initiation of RRT, and initial use of continuous RRT. After adjustment, such practice variation was associated with lower ICU and hospital stay and 90-day mortality among ANZ patients compared with other regions.


Normality of the data
Based on the central limit theorem, with a sample size of >2500 patients, we can assume that the distribution of sample means approximates a normal distribution regardless of the population's distribution.In addition, for the analyses of continuous variables we used median regression that is less impacted of non-normality of the data.

Selection of variables for sensitivity analyses
As a sensitivity analysis, an additional multivariable model included all variables with a P<0.05 at baseline and study site as a random effect.However, premorbid urine analysis and pre-randomization positive end-expiratory pressure (PEEP) were not included due to a high degree of missing data.Additionally, the initial RRT modality was not included because this was an exposure of interest that could explain the practice differences.Also, pre-randomization mechanical ventilation was not included because it was systematically missing in one specific country (missing not at random).Risk difference calculated from a multivariable generalized linear model with binomial distribution and identity link.
Median difference calculated from a multivariable median regression using an interior point algorithm.
All models adjusted for age, sex, SAPS II, type of admission (surgical vs. medical), presence of sepsis and cumulative fluid balance pre-randomization.Sites were entered as random effect.Abbreviations: ICU is intensive care unit; RRT is renal replacement therapy; MAKE is major adverse kidney events; RD is risk difference; MD is median difference.
Risk difference calculated from a multivariable generalized linear model with binomial distribution and identity link.
Median difference calculated from a multivariable median regression using an interior point algorithm.
All models adjusted for age, sex, SAPS II, type of admission (surgical vs. medical), presence of sepsis and cumulative fluid balance pre-randomization.Sites were entered as random effect.
Data are median (quartile 25 th -quartile 75 th ) or N (%).* Including pre-randomization fluid balance eFigure1 -Fluid balance accross regions according to severity of illness RRT: renal replacement therapy, SAPS: simplified acute physiology score

Regional Practice Variation and Outcomes in the STARRT-AKI trial: A Post-hoc Secondary Analysis
Fluid Balance in the First 14 Days Across Geographic Regions in the Medical and Surgical Patient Subgroups.
eTable 4 -Univariable Models for Key Outcomes eTable 5 -Full Multivariable Models for Key Outcomes eTable 6 -Clinical Outcomes of Medical Patient Subgroup eTable 7 -Multivariable Models for Key Outcomes of Medical Patient Subgroup eTable 8-Clinical Outcomes with Cardiac Surgery Patients Excluded eTable 9 -Multivariable Models for Key Outcomes with Cardiac Surgery Patients Excluded eTable 10 -Clinical Outcomes with Elective Surgical Patients Excluded eTable 11 -Multivariable Models for Key Outcomes with Elective Surgical Patients Excluded eTable 12 -Full Multivariable Models for Key Outcomes (Accelerated-Strategy Arm) eTable 13 -Full Multivariable Models for Key Outcomes (Standard-Strategy Arm) eTable 14 -Summary of baseline characteristics between France and the rest of Europe eTable 15 -Fluid Balance in the First 14 Days (France vs. Rest of Europe) eTable 16 -Multivariable Models for Key Outcomes (France vs. rest of Europe) eTable 17 -Full Multivariable Models for Key Outcomes (France vs. rest of Europe) eFigure1 -Fluid balance accross regions according to severity of illness eFigure 2 -Kaplan-Meier Curves of 90-Day Survival According to Geographic Region and Randomization Arm eFigure 3 -Renal Replacement Therapy-Free Days According to Geographic Region STARRT-AKI Investigators

Fluid Balance in the First 14 Days Across Geographic Regions in the Medical and Surgical Patient Subgroups.
Data are median (quartile 25 th -quartile 75 th ) or N (%).Abbreviation: SOFA is Sequential Organ Failure Assessment; SAPS II is Simplified Acute Physiology Score II; AKI is acute kidney injury; eGFR is estimated glomerular filtration fraction; SOFA is Sequential Organ Failure Assessment; CFS is clinical frailty score; PEEP is positive end-expiratory pressure; RRT is renal replacement therapy.

Univariable Models for Key Outcomes
Abbreviations: ICU is intensive care unit; RRT is renal replacement therapy; modified MAKE is major adverse kidney events inclusive of RRT at 90 days and mortality only; RD is risk difference; MD is median difference VFD is ventilator free days Risk difference calculated from a univariable generalized linear model with binomial distribution and identity link.Median difference calculated from a univariable median regression using an interior point algorithm.eTable5 -

Full Multivariable Models for Key Outcomes North America vs. Europe ANZ vs. Europe ANZ vs. North America
Abbreviations: ICU is intensive care unit; RRT is renal replacement therapy; MAKE is major adverse kidney events; RD is risk difference; MD is median difference; VFD is ventilator free days Risk difference calculated from a multivariable generalized linear model with binomial distribution and identity link.Median difference calculated from a multivariable median regression using an interior point algorithm.All models adjusted for age, weight, SAPS II, type of admission (surgical vs. medical), admission diagnosis, hypertension, diabetes, heart failure, liver disease, cardiopulmonary bypass, aortic surgery, IV contrast, aminoglycoside, presence of sepsis, premorbid eGFR, pre-randomization total SOFA, clinical frailty score, pre-randomization respiratory rate, pre-randomization cumulative fluid balance, pre-randomization pH, prerandomization creatinine, pre-randomization hemoglobin, pre-randomization platelets, pre-randomization noradrenaline use, pre-randomization diuretic use.Sites were entered as random effect.eTable6 -

Multivariable Models for Key Outcomes of Medical Patient Subgroup North America vs. Europe ANZ vs. Europe ANZ vs. North America
Data are median (quartile 25 th -quartile 75 th ) or N (%).Abbreviation: ICU is intensive care unit; RRT is renal replacement therapy.eTable7-Abbreviations:ICU is intensive care unit; RRT is renal replacement therapy; MAKE is major adverse kidney events; RD is risk difference; MD is median difference.Risk difference calculated from a multivariable generalized linear model with binomial distribution and identity link.Median difference calculated from a multivariable median regression using an interior point algorithm.All models adjusted for age, sex, SAPS II, type of admission (surgical vs. medical), presence of sepsis and cumulative fluid balance pre-randomization.Sites were entered as random effect eTable 8-

eTable 9 -Multivariable Models for Key Outcomes with Cardiac Surgery Patients Excluded
Abbreviations: ICU is intensive care unit; RRT is renal replacement therapy; MAKE is major adverse kidney events; RD is risk difference; MD is median difference.

eTable 12 -Full Multivariable Models for Key Outcomes (Accelerated-Strategy Arm)
Abbreviations: ICU is intensive care unit; RRT is renal replacement therapy; MAKE is major adverse kidney events; RD is risk difference; MD is median difference; VFD is ventilator free days Risk difference calculated from a multivariable generalized linear model with binomial distribution and identity link.Median difference calculated from a multivariable median regression using an interior point algorithm.All models adjusted for age, weight, SAPS II, type of admission (surgical vs. medical), admission diagnosis, hypertension, diabetes, heart failure, liver disease, cardiopulmonary bypass, aortic surgery, IV contrast, aminoglycoside, presence of sepsis, premorbid eGFR, pre-randomization total SOFA, clinical frailty score, pre-randomization respiratory rate, pre-randomization cumulative fluid balance, pre-randomization pH, prerandomization creatinine, pre-randomization hemoglobin, pre-randomization platelets, pre-randomization noradrenaline use, pre-randomization diuretic use.Sites were entered as random effect.

eTable 13 -Full Multivariable Models for Key Outcomes (Standard-Strategy Arm)
Abbreviations: ICU is intensive care unit; RRT is renal replacement therapy; MAKE is major adverse kidney events; RD is risk difference; MD is median difference; VFD is ventilator free days Risk difference calculated from a multivariable generalized linear model with binomial distribution and identity link.Median difference calculated from a multivariable median regression using an interior point algorithm.All models adjusted for age, weight, SAPS II, type of admission (surgical vs. medical), admission diagnosis, hypertension, diabetes, heart failure, liver disease, cardiopulmonary bypass, aortic surgery, IV contrast, aminoglycoside, presence of sepsis, premorbid eGFR, pre-randomization total SOFA, clinical frailty score, pre-randomization respiratory rate, pre-randomization cumulative fluid balance, pre-randomization pH, prerandomization creatinine, pre-randomization hemoglobin, pre-randomization platelets, pre-randomization noradrenaline use, pre-randomization diuretic use.Sites were entered as random effect.

eTable 15 -Fluid Balance in the First 14 Days (France vs. Rest of Europe)
Data are median (quartile 25 th -quartile 75 th ) or N (%).Abbreviation: SOFA is Sequential Organ Failure Assessment; RRT is renal replacement therapy; SAPS II is Simplified Acute Physiology Score II; CRRT is continuous renal replacement therapy; IHD is intermittent hemodialysis; SLED is slow low efficiency daily dialysis; AKI is acute kidney injury; eGFR is estimated glomerular filtration fraction; SOFA is Sequential Organ Failure Assessment; CFS is clinical frailty score; PEEP is positive end-expiratory pressure; RRT is renal replacement therapy.